Despite significant improvements in the care of patients with ESRD, mortality remains very high. Vascular disease is the major culprit and is also the leading cause of morbidity {{3464}}. Although more than one disease process is involved and the causes are multiple, vascular calcification is prevalent and is certainly an important factor. This calcification occurs in the media of large and small arteries and is also known as Monckeberg's arteriosclerosis. In addition to causing or contributing to ischemic events, the calcification can decrease arterial compliance and thereby lead to increased pulse pressure, which is a strong risk factor for death in ESRD. Arterial calcification can also impair the dilatation necessary to supply the arteriovenous fistulae and grafts for hemodialysis. The clinical approach to this problem remains the control of circulating calcium and phosphate concentrations despite the fact that it is unproven and abundant data now indicate that deficiencies of endogenous inhibitors of calcification play an important role. We have recently shown, in a new model system using cultured rat aorta, that pyrophosphate is an important endogenous inhibitor of vascular calcification. We have also found that plasma pyrophosphate levels are reduced in hemodialysis patients and decline further during dialysis, suggesting that strategies to prevent vascular calcification in ESRD should be based on the detection and correction of local or systemic pyrophosphate deficiency. The goals of this proposal are to determine the cause of PPi deficiency in uremic vascular smooth muscle, to PPi and bisphosphonates prevent vascular calcification in vitro and in vivo, and to determine the cause and clinical significance of reduced plasma PPi levels in patients with renal failure. These aims will be addressed with studies in vivo in both humans and animals, and in studies in vitro in cultured rat aorta. We will combine metabolic studies of PPi in rat aortas with kinetic studies of plasma pyrophosphate in humans. The findings will be correlated with vascular calcification in patients, quantitated by abdominal CT scanning and mammography. The results will establish a new paradigm for vascular calcification in renal failure and form the basis for important clinical trials in humans.